27 September 2006. Schizophrenia and bipolar disorder are debilitating psychiatric diseases with considerable overlap. They share multiple symptoms, and there is evidence that both occur in the same extended families more often than predicted by chance. This has led to the theory that variations within certain genes can increase susceptibility to both diseases (see SRF live discussion). Though the search for such susceptibility variations can be extremely complex—carriers are most often completely normal, for example, making it difficult to trace who does and who does not have a disease variant—researchers in Europe and the U.S. have just added two new genetic loci to the list of those linking schizophrenia and bipolar disorder.

In an article published online September 19 in Human Molecular Genetics, a collaboration led by Hamid Mostafavi Abdolmaleky and Sam Thiagalingam at Boston University, and Ming Tsuang at Harvard University, and comprising researchers from those and several other institutions, reports that reduced methylation of a gene coding for membrane-bound catechol-O-methyltransferase (MB-COMT), an enzyme that plays a crucial role in degrading the neurotransmitter dopamine and other catecholamines, is a major risk factor for the two diseases. In addition, a paper published online September 12 in Molecular Psychiatry, by Giovanni Vazza and colleagues at the University of Padova in Italy, identifies a shared susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26. Together, the papers not only strengthen the connection between the two disorders, but the COMT data also help explain the molecular basis for both, as well as shedding light on how the environment may influence a person’s chance of developing schizophrenia or bipolar disorder.

Too much degradation?The identification of COMT as a susceptibility locus is not unexpected. Two variants of the COMT gene, differing by a single letter of genetic code, were previously identified, and one of them, producing a valine instead of a methionine at amino acid position 158 of the protein, was linked to schizophrenia (see SRF related news story). But in finding that the COMT gene in schizophrenia and bipolar patients is poorly methylated, Abdolmaleky and colleagues add a new twist. While this chemical modification has no effect on the genetic code itself, it can dramatically change gene activity by preventing DNA from interacting with the machinery that converts the genetic code into protein. In keeping with this, the researchers found that in postmortem samples of dorsolateral prefrontal cortex taken from 35 schizophrenia and 35 bipolar patients, the promoter region of MB-COMT—the very switch that turns on and off the gene—is the one that is poorly methylated. (Note: separate promoters generate membrane-bound and soluble COMT from the same gene.)

In theory, hypomethylation of the MB-COMT gene promoter could lead to increased gene activity, elevated COMT enzyme in the brain, and increased degradation of dopamine, perhaps explaining the loss of this neurotransmitter in the brains of schizophrenia patients (see Akil et al., 1999 and SRF related news story). In support of this idea, Abdolmaleky and colleagues used a cell-based assay to confirm earlier data that hypomethylation of COMT does indeed lead to increased gene expression, and they also compared the amount of COMT mRNA in brain extracts from schizophrenia patients and age-matched controls. Quantitative DNA amplification following reverse transcription revealed that COMT mRNA levels in patients were significantly higher in patients than controls (almost threefold in samples from the Harvard Brain Tissue Resource Center, though not as great a difference in samples from the Stanley Medical Research Institute). The researchers also found an inverse relationship between the levels of COMT and dopamine receptor DRD1 expression that translates into an overall hypoexpression of DRD1 in patients. Taken together, the data suggest that COMT and DRD1 levels may conspire to deprive patients of sufficient dopaminergic transmission.

Like all susceptibility variations, the effect of the MB-COMT hypomethylation is not all-or-none. The researchers found that the gene promoter was hypomethylated in 40 percent of controls compared to 74 and 71 percent of schizophrenia and bipolar patients, respectively. Interestingly, when Abdolmaleky and colleagues separately measured methylation status in samples from the left and right hemispheres of the brain, they found that the patient/control differences were more pronounced in the left side of the brain. In controls, hypomethylation of the promoter only occurred 20 percent of the time in the left side of the brain as opposed to 59 percent in the right side. This seems to suggest that the left side may be more susceptible to changes in methylation status, which would fit with the important role of the left hemisphere in schizophrenia. The language center of the brain is located in the left hemisphere in most people, and many of the symptoms of the disease have been linked to loss of brain laterality and to language difficulties. The loss of brain laterality of MB-COMT promoter methylation in the patients is consistent with other evidence indicating that brain laterality is lost in schizophrenia and bipolar patients (e.g., Crow, 1990).

But the methylation link speaks to a much broader theme, namely the cross-talk between the environment and genetic regulation. Environmental stimuli can cause profound changes in gene expression and behavior due to methylation or demethylation of specific genes (see SRF related news story). This paper hints at a disease/environment nexus that impacts COMT methylation. In fact, the researchers addressed this issue, correlating alcohol use with MB-COMT promoter modification in the patients. They found that methylation was more likely in heavy and moderate alcohol consumers. However, this trend could not be tracked in controls, as heavy and moderate alcohol abuse was not frequent in the control subjects.

The authors note that the sample size in this study was fairly small. “Our analyses reported here provide a clear trend that needs to be further validated in a larger population in future studies,” they write. This includes their finding that the valine allele at position 158 of the COMT enzyme seems to be enriched in samples that also have the promoter hypomethylation. The valine variant is a more active enzyme than that with methionine at the same position, suggesting that patients may be doubly impacted, first by overproduction of the protein, and second, by the fact that the protein is more active than normal.

In the second paper, Vazza and colleagues report that an as-yet uncharacterized locus on a small segment of chromosome 15 links to schizophrenia, bipolar disorder, and schizoaffective disorder in a small group of families in northeastern Italy. The locus lies very close to the ST8SIA2 gene, coding for sialyltransferase 8B, which was recently linked to schizophrenia in a Japanese population (see Arai et al., 2005).

Vazza and colleagues performed genome-wide analysis on 57 individuals in 16 families originating from Chioggia, a “culturally closed” community on an island in the Venetian lagoon. Seven families had only schizophrenia patients, two families had only bipolar patients, and the other seven families had members with two or more of the three disorders. The researchers identified four potential susceptibility loci on chromosomes 1p36, 1q43, 4p14, and 15q26. Only the latter stood up to rigorous statistical analysis, giving a logarithm of odds score greater than 3.0.

Though it lies close to the ST8SIA2 gene, this new 15q26 locus lies about 5Mb away. Furthermore, when Vazza and colleagues analyzed ST8SIA2 single nucleotide polymorphisms (SNPs) that were linked to schizophrenia in the Japanese study, they found no difference between SNP frequencies in the Chioggia population and control populations from other Italian regions. The data indicate that there may be another gene on chromosome 15q that confers susceptibility to schizophrenia and bipolar disorder.—Tom Fagan.

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.